Abstract
The artemisinin class of anticancer compounds is well known for oxidative DNA-damage-mediated growth arrest, followed by cell death. However, the nature of this genotoxic stress for cancer therapeutics remains elusive. Here we show that artesunate (Art), a water-soluble artemisinin analog, triggers inducible anticancer responses directly implicated in the DNA-damage-intended therapy. We observed that the level of the antiviral enzyme APOBEC3C (apolipoprotein-B mRNA-editing catalytic polypeptide-like 3C (A3C)) preferentially increased upon the treatment with Art against tumor xenografts of p53-deficient H1299 cells. Using gain-of-function experiments, A3C could improve the therapeutic efficacy of Art, as determined by cell proliferation and colony formation assays. Furthermore, elevated A3C provoked a minor accumulation of γH2AX foci and the phosphorylation of RPA32 and Chk1, which strongly sensitized H1299 cells to Art. The employment of A3C also caused an increase in the synergistic interaction between Art and Chk1 inhibition. Besides, A3C overexpression delayed the cell cycle at the S phase, accompanied by attenuated G2/M arrest in the presence of Art. The enzymatic inactivation of A3C by the mutation of zinc-coordinating residues (C97S and C100S) indicated that A3C sensitized Art in a deaminase-dependent manner. Furthermore, we showed that using small interfering RNA against A3C can induce the chemoresistance of Art. These studies combine to suggest that upregulated A3C is involved in the Art-induced DNA damage response as a consequent event to improve the overall cytotoxic responses of Art.